Pneumonia is one of the most common nosocomial infections, causing significant morbidity and mortality in the United States for patients in the intensive care unit and extending hospitalization costing billions of dollars annually. Currently, the gold standard for the diagnosis of pneumonia is based upon results from a bacterial culture. This process takes approximately 72 hours. During this 72 hour waiting period, the patient is empirically administered broad-spectrum antibiotics.
Sepsis is the leading cause of morbidity and mortality in surgical intensive care units. Despite recent advances in treatment and management, about 1.1 million hospitalized patients develop sepsis annually in the United States, with an accompanying annual mortality rate of 28.6%. Sepsis and its associated complications remain an enormous economic burden on the health care system, with total annual costs exceeding $1.4 billion USD nationally. Due to several high-profile fatalities, the high mortality rates in general, and high associated costs, sepsis continues to remain a serious concern to health-care providers.
While clinical and experimental studies have dramatically increased the understanding of the pathogenesis of both pneumonia and sepsis, the standard of care remains largely supportive, coupled with the use of antibiotics. With an increasing number of patients becoming infected with antibiotic-resistant bacteria, novel non-antibiotic treatments are urgently needed to combat pneumonia and sepsis.
During pneumonia and sepsis, exquisite control of the inflammatory response is necessary to promote an anti-microbial response and minimize tissue injury. Activated leukocytes are essential for the anti-microbial response, but can become unresponsive or undergo apoptosis over the course of these infections. In other inflammatory states, both activated and apoptotic leukocytes have been shown to generate microparticles (hereinafter “MPs”). Although MPs are normally found in the circulation of healthy individuals, changes in the quantity and type of circulating MPs have been observed in individuals with ongoing inflammation.
At the onset, lung bacterial infection and sepsis are both characterized by robust leukocyte recruitment and the release of inflammatory mediators, which in pneumonia are responsible for alveolar damage, edema, and impaired oxygen transport, and in sepsis are response fro hypoperfusion and organ dysfunction. As the disease state persists, a shift towards an anti-inflammatory state is observed, and patients can develop features consistent with immune suppression. An important hallmark of immune suppression is profound immune cell apoptosis. One consequence of this is ingestion of apoptotic, phosphatidyl serine-expressing bodies by phagocytes and the subsequent secretion of anti-inflammatory cytokines such as TGF-β, PGE2 and IL-10. Thus, leukocyte apoptosis and ingestion can lead to a reduced number of cells available for mounting an anti-microbial response as well as increasing levels of anti-inflammatory cytokines. This immune suppression, coupled with increasing cases with antibiotic resistant bacteria, represent a significant risk for increased mortality and morbidity for patients in intensive care units.
One possible inflammatory mediator of infection is MPs. MPs have long been termed “platelet dust” and considered inert debris reflecting cellular activation or damage. MPs are small intact vesicles derived from cell membranes and vary in size from 0.3-1.0 μm. The most studied MPs in the blood are derived from platelets, although peripheral and tissue MPs can also arise from lymphocytes, myeloid cells, endothelial cells, and red blood cells. MPs are easily separated and distinct from exosomes and cellular debris by differential centrifugation. MPs display membrane proteins implicated in a variety of fundamental processes and thus may constitute a disseminated pool of bioactive effectors. They are thought to contribute to hemostatic and inflammatory responses, vascular remodeling and angiogenesis, cell survival, and apoptosis.
Activation and cellular death are the proposed methods of MP generation, though the exact mechanisms of these processes are still unclear. During cell activation, remodeling of the plasma membrane can take place. This membrane modification can cause bleb formation, leading to the extrusion of MPs which incorporate surface proteins and other contents of the originating cell. MP release is also associated with cell apoptosis and may occur at the same time as cell fragmentation and the formation of apoptotic bodies.
Septic shock is characterized by an overwhelming release of inflammatory mediators, which are responsible for organ dysfunction and hypoperfusion. However, as sepsis persists, a shift towards an anti-inflammatory state is observed, and patients develop features consistent with immune suppression. Interestingly, 70% of septic non-survivors are still alive 3 days after the onset of the pro-inflammatory phase of septic shock. Approximately 80% of septic non-survivors had a continuous septic focus at time of death. Taken together, it is believed that the majority of shock-related deaths occur during this immune-compromised state in which the ability to eradicate infectious microorganisms is reduced. An important hallmark of immune suppression is profound immune cell apoptosis. One consequence of this is ingestion of apoptotic, phosphatidyl serine-expressing bodies by phagocytes and the subsequent secretion of anti-inflammatory cytokines such as TGF-β, PGE2 and IL-10. Leukocyte apoptosis and ingestion can lead to a reduced number of cells available for mounting an anti-microbial response as well as increasing levels of anti-inflammatory cytokines. This immune suppression, coupled with increasing cases with antibiotic-resistant bacteria, represent a significant risk for increased mortality and morbidity for patients in intensive care units.
The ineffectiveness of current interventions to better ameliorate the impact of sepsis upon patients in the intensive care unit demonstrates that more knowledge of the pathophysiology of sepsis is needed to develop more successful therapies. While studies have dramatically increased the understanding of sepsis pathogenesis, the standard of care remains largely supportive.